2 May 2017

Translational Trends - SIRENE: silencing microRNAs to attenuate the progression of heart failure

Heart failure is a serious clinical disorder that still represents the primary cause of hospitalisation and death in Europe. Several cardiovascular conditions, including hypertension, coronary artery disease and genetic forms of cardiomyopathies, result in heart failure. While conventional pharmacological treatment strategies (e.g., β-blockers, ACE-inhibitors) have shown effectiveness in prolonging survival of heart failure patients, the prognosis of affected individuals remains poor, leaving a desperate need for new therapeutic concepts. 

Adverse cardiac hypertrophy is the principal risk factor for the development of heart failure and lethal arrhythmias. A complex web of interconnected signalling pathways has been implicated in cardiac hypertrophy and species of non-coding RNA molecules, such as microRNAs, have been shown to regulate these pathways. Data obtained from the Dutch Heart Foundation-funded CVON-ARENA consortium on the biological processes causing this disease mark a principal step towards new therapeutic concepts. By counteracting the expression (amount) and activity of single microRNAs in the heart, this consortium has demonstrated that it is possible to prevent, delay and even reverse heart disease in robust animal models of disease. 

The recognition of microRNAs as drug-able therapeutic targets resulted in the founding of Mirabilis Therapeutics BV, a CARIM/MUMC+ spin-off drug development company in 2015. Mirabilis has dedicated the majority of its efforts in the past 2 years to optimize the chemistry of antisense oligonucleotides and test the pharmacological properties of various microRNA inhibitors. Mirabilis’ lead compound, MRB-8001, an optimized inhibitor of microRNA-199b, has now advanced through efficacy studies in rat and pig models of heart failure. 

The public-private “SIRENE” project, awarded to Leon de Windt and his team at CARIM with €600.000 by The Programme Translational Research (PTO) of Netherlands Organisation for Health Research and Development (ZonMW) and by Mirabilis Therapeutics, will move these preclinical findings to the next stage. Following preclinical safety/toxicity testing, the overarching objective of the SIRENE project is to perform a first-in-man Phase I study in healthy volunteers to evaluate the safety and tolerability of MRB-8001, which will enable us to subsequently investigate the efficacy of MRB-8001 in a future Phase II trial in hypertensive heart failure patients. Besides the continuing need for mechanistic insights generated by basic microRNA research, the SIRENE project will aid the transition of knowledge from bench to bedside and transform microRNA-based therapeutics into an expected clinical reality.